PB1796: ADMINISTRATION OF A KETOGENIC DIET FOR CHEMOTHERAPY PROTECTION IN ACUTE LEUKEMIA PATIENTS: IS IT FEASIBLE, SAFE, AND VALUABLE? PRELIMINARY RESULTS OF THE RANDOMIZED CONTROLLED TRIAL LEU-KETO STUDY.
Authors: Maria Lastra Cagigas, Gayathiri Rajakumar, Kristen Skarratt, Rachael Hayward, Tiana Pelaia, Alireza Ardjmand, Lachlin Vaughan, Luigi Fontana, Stephen Fuller
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute myeloid leukemia (AML) is a highly aggressive hematological cancer treated with intensive chemotherapy. The combination of cytarabine and anthracyclines causes non-selective severe damage and cell death in malignant and healthy tissues. The toxicity can lead to profound malfunctioning and failure of fast-proliferating tissues, particularly of the immune system and gastrointestinal tract, among others. There are currently no strategies to protect from this toxicity. Preclinical studies show that inhibiting the key pro-proliferative signalling node mTOR reduces chemotherapy-induced damage and activates cellular repair pathways in healthy cells. This inhibition of the insulin/IGF-1/mTOR pathway can be achieved by consuming a ketogenic diet that primarily deprives the body of glucose and induces ketosis. Therefore, we hypothesize that metabolic ketosis will reduce chemotherapy-induced damage and side effects in patients with AML. In addition, ketosis will sensitize AML blasts to chemotherapy due to their dysregulated ketone metabolism. Aims: The LEU-KETO study aims to examine the feasibility, safety, and chemo-protective capacity of a high-fat ketogenic diet administered prior to and during induction chemotherapy in AML patients. Methods: Eligible patients with de novo AML were randomized to receive either a control or ketogenic (intervention arm) diet upon hospital admission. Blood, urine, medical progress, and dietary questionnaires were collected from baseline to complete neutrophil recovery (approximately 1 month). Bone marrow was collected at admission and discharge. Healthy immune cells and malignant blasts were isolated and analyzed for changes in cell proliferation and death, DNA damage, and cellular senescence using flow cytometry. Ketone bodies and glucose were measured to evaluate dietary compliance. Side effects, WBC, RBC, and platelet recovery were monitored to assess safety and chemo-protection. Results: Preliminary data from patients (n = 8) show the ketogenic diet is well tolerated and induces mild ketone production. Clinical remission, characterized by an absence or very low level of blasts post-chemotherapy, was achieved in 3/3 of the patients who completed the intervention arm, suggesting that the ketogenic diet does not impair chemotherapy efficacy. Indeed, leukemic cells in subjects consuming the ketogenic diet showed increased DNA damage as indicated by higher levels of y-H2AX expression compared to the controls. The intervention arm displayed normal WBC, RBC, and platelet recovery, and decreased cellular senescence in healthy lymphocytes. Summary/Conclusion: Pilot results suggest metabolic ketosis is compatible with induction chemotherapy for AML patients and it increases DNA damage in leukemic blasts while offering protection from senescence to healthy lymphocytes. No detrimental diet-induced side effects were observed, making the nutritional intervention a promising first-line adjuvant therapy for the treatment of AML.Keywords: Clinical trial, Chemotherapy toxicity, DNA damage, Acute myeloid leukemia